During the current SCOR period, significant progress has been made to elucidate the mechanism of lupus autoantibody diversification and to identify important HLA-D restriction elements in response to SLE-related autoantigens. Crossreactive autoantibodies and the expansion of antigen-specific T cells reactive to one or more SLE-related autoantigens are important in the diversification of autoantibody response. With current available transgenic mice expressing D region molecules, DR2 and DR3 are the dominant determinants controlling the magnitude of the precipitating antibody response to recombinant ROM and for intermolecular epitope spreading to Ro52. For SmD immunization, DR3 was shown to be dominant with the generation of specific antibodies for SmB. This competitive renewal application is to continue to explore the role of HLA-D region and T cell epitopes in SLE-related autoantigens in the pathogenesis of SLE. Four specific aims are proposed: Specific Aim 1: To use the existing transgenic HLA-DR3 and -DR4 mouse to map further the T cell epitopes on Ro60, SmD, SmB and the A protein of the snRNP particle, by generation of antigen-specific TT hybridomas. Specific Aim 2: To study antigenspecific T cells by HLA-DR3 and HLA-DR4 SLE patients and matched controls by HLA-DR tetramers loaded with SLE-related antigenic peptides. This is a collaboration between UVa and Virginia Mason Research Center. Specific Aim 3: To generate NZM2328 mutants which lack the entire mouse I region and express the various HLA-D region molecules as transgenes to determine whether these transgenes can support the spontaneous autoantibody generation and the induction of acute and chronic glomerulonephritis. They will also be tested to determine whether chronic sialoadenitis can be induced by CMV. Specific Aim 4: To initiate a collaborative study to compare the antiSm antibody specificity in the SLE populations of northern India and central Virginia. Both patients and matched normal controls will be HLA- typed and studies as outlined in Aim 2 will be performed. The results obtained in these experiments will provide a basis for further exploration of the importance of the molecular mimicry in the pathogenesis of SLE. It might also provide newer insight into autoantibody diversification and the generation of end-organ damage in this disease.